Pediatrics

Non-Hodgkins

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Non-Hodgkins Lymphoma? What are the typical findings for this disease?

Pediatric Non-Hodgkins Lymphoma (NHL) includes a group of malignancies arising from lymphoid cells and organs. NHL can affect children at any age. Children generally present with adenopathy and systemic symptoms such as fever and weight loss. NHL can progress very rapidly and must be evaluated and managed urgently.

Pediatric NHL includes Burkitt Lymphoma, Diffuse Large B-Cell Lymphoma, Lymphoblastic Lymphoma, Anaplastic Large Cell Lymphoma, and other more unusual lymphomas which should be histologically confirmed prior to treatment whenever possible. Each type of NHL requires different treatment and has variable outcomes. Treatment includes multiagent systemic chemotherapy and central nervous system prophylaxis. Newly diagnosed patients are at high risk for tumor lysis syndrome.

NHL is a diverse collection of malignancies arising from lymphoid cells and organs.

B-cell, T-cell, or NK cell origin

Differentiated by morphology, flow cytometry, and cytogenetics

Typically high grade in children

Variety of therapy depending on histologic type

Variety of outcomes

Pediatric NHL is distinct from NHL that occur in adults.

Different subtypes, staging, biology, treatment, and prognosis

Typical findings:

Painless lymphadenopathy

Abdominal pain or swelling

Breathing problems

Fever

Bleeding

Bruising

Weight loss

Symptoms can progress very rapidly. In general, lymph nodes that are in unusual locations (beyond cervical and inguinal), larger than 2 cm, rapidly increasing in size, or matted together are more concerning for malignancy including NHL.

What subtypes of NHL occur in children?

Mature B-cell orgin

Burkitt Lymphoma

Diffuse Large B-cell Lymphoma (DLBCL)

Primary Mediastinal B-cell Lymphoma

Lymphoblastic Lymphoma

Presursor T-cell

Precursor B-cell

Anaplastic Large Cell Lymphoma (ALCL)

ALK positive

ALK negative

Rare Lymphomas in pediatrics

Mature (Peripheral) T-cell Lymphoma

Follicular Lymphoma

Primary cutaneous lymphoma

Marginal zone lymphoma (MZL)

Nodal MZL

Mucosa Associated Lympoid Tumor (MALT) Lymphoma

Post transplant Lymphoproliferative Disease (PTLD)

Primary Central Nervous System (CNS) Lymphoma

What is the difference between lymphoma and leukemia?

Lymphoma and leukemia arise from the same group of hematopoietic cells.

Defined by percentage of bone marrow involvement at the time of diagnosis.

How are lymphoblastic lymphomas treated?

Lymphoblastic lymphomas are treated similarly, often on the same clinical trial, as lymphoblastic leukemia of the same cell type (precursor B-cell or T-cell).

Risk stratification is not as well established as for lymphoblastic leukemia

Therapy is the same for all stages of disease

Therapy is 2 or 3 years depending on therapeutic protocol.

May be longer for boys

Three phases of therapy

Remission induction (1 month)

Intensive cytoreductive chemotherapy

Consolidation (6 to 9 months)

Intensive cytoreductive chemotherapy

Intensive CNS prophylaxis with intrathecal chemotherapy

Cranial radiation typically not indicated – unless there is CNS disease at diagnosis

Maintenance (1 to 2 years)

Lower dose antimetabolite based chemotherapy

How is anaplastic large cell lymphoma treated?

Treatment is more variable than for other subtypes of pediatric NHL.

Grossly resected low stage disease

Typically can be treated with short term pulsed therapy similar to mature B-cell NHL.

Isolated cutaneous disease may be able to be treated with surgical resection only if ALK-negative.

Disseminated disease

Currently, in the United States, most often treated with APO regimen.

Anthracycline, prednisone, and vincristine based chemotherapy

5 weeks of induction therapy

45 weeks of consolidative therapy in 3 week cycles

New protocol in the United States will transition to approach more similar to German group.

Interest in new agents

New anti-CD30 monoclonal antibody

Development of specific ALK inhibitor

How is recurrent or refractory NHL treated?

The optimal strategy for how to treat children with recurrent disease or refractory to initial chemotherapy is not clear. As no standard treatment currently exists, all children should be considered for participation in a clinical trial if one is available.

Ongoing clinical trials and laboratory investigations are looking for new agents and therapeutic approaches.

Particular interest in investigation into small-molecule inhibitors of intracellular targets.

What are the adverse effects associated with each treatment option?

Tumor Lysis Syndrome

See previous section on prevention and treatment of tumor lysis syndrome.

Immediate effects of chemotherapy

Common side effects of chemotherapy include nausea/vomiting, alopecia, and hematologic suppression. Hematologic suppression can result in fatigue (anemia), bleeding (thrombocytopenia), and risk for infection (neutropenia).

In extreme situations, empiric treatment (most commonly with corticosteroids) may be indicated prior to obtaining tissue for pathology.

Are additional laboratory studies available; even some that are not widely available?

N/A

How can Non-Hodgkins Lymphoma be prevented?

There are no known preventive strategies for pediatric NHL.

What is the evidence?

Gross, TG, AM Termuhlen. “Pediatric Non-Hodgkin's Lymphoma”. Current Oncology Reports. vol. 9. 2007. pp. 459-465.. (This is an overview of pediatric NHL focusing on the differences from adult and pediatric disease and discussing in detail current recommendations for treatment for common pediatric subtypes.)

Howard, SC, Jones, DP, Pui, C. “The Tumor Lysis Syndrome”. New England Journal of Medicine. vol. 364. 2011. pp. 1844-54.. (This is a review of the biology, definition, and management of tumor lysis syndrome written from the pediatric perspective. TLS is an important complication during early treatment for NHL that may need to be recognized and managed by non-oncology physicians.)

Link, MP, Shuster, JJ, Donaldson, SS. “Treatment of children and young adults with early-stage non-Hodgkin's lymphoma”. New England Journal of Medicine,. vol. 337. 1997. pp. 1259-66.. (This article presents the rational for currently recommended treatment approaches for pediatric patients with low stage NHL stressing that minimal therapy is likely to be adequate for disease control with few late effects. This article demonstrates no benefit of radiation to tumor sites. This article also reviews the important finding that lymphoblastic lymphoma requires longer therapy similar to lymphoblastic leukemia.)

Laver, JH, Kraveka, JM, Hutchison, RE. “Advanced-stage large-cell lymphoma in children and adolescents: results of a randomized trial incorporating intermediate-dose methotrexate and high-dose cytarabine in the maintenance phase of the APO regimen: a Pediatric Oncology Group phase III trial”. Journal of Clinical Oncology. vol. 23. 2005. pp. 541-547.. (This article presents the results of the most recent United States therapeutic trial for ALCL. The results suggest that the addition of methotrexate and cytarabine does not improve results when compared to standard chemotherapy with APO regimen.)

Gross, TG, Hale, GA, He, W. “Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents”. Biology of Blood and Marrow Transplant. vol. 16. 2010. pp. 223-30.. (This study reviewed all stem cell transplants for refractory or recurrent pediatric NHL that were reported to the Center for International Blood and Marrow Transplant Research. Data on 182 transplants worldwide was reviewed for transplant characteristics and outcomes. Transplant appears to be an effective salvage therapy for relapsed and refractory NHL.)

Mahadevan, D, Fisher, RI. “Novel Therapeutics for Aggressive Non-Hodgkin's Lymphoma”. Journal of Clinical Oncology,. vol. 29. 2011. pp. 1876-1884. (This is a review of the development of new targeted therapeutic agents for NHL focusing on potential small-molecule inhibitors of intracelluar targets. These approaches may be relevant to both children and adults with NHL particularly those with relapsed or refractory disease.)

“Childhood Non-Hodgkin Lymphoma Treatment, Physician Data Query, National Cancer Institute,”. (This is a website maintained by the National Cancer Institute to provide up-to-date information on pediatric NHL and its treatment written for both patients and health professionals. Information on this site is updated monthly by national experts in the field.)

Ongoing controversies regarding etiology, diagnosis, treatment

Clinical trials to optimally treat pediatric NHL are ongoing through the Children’s Oncology Group and other international pediatric oncology cooperative groups. Work continues on better risk stratification, development on new chemotherapy agents and strategies particularly for recurrent or refractory disease, and minimization of long-term effects of therapy.